Increased Poly(ADP-Ribosyl)ation in Peripheral Leukocytes and the Reperfused Myocardium Tissue of Rats With Ischemia/Reperfusion Injury

Abstract

The overactivation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) is considered a final common effector in ischemia/reperfusion (I/R) injury. The aim of the current study was to examine the precise time course of the activation of PARP in peripheral leukocytes and the reperfused myocardium tissue on myocardial I/R injury from the same rat and to identify the relationship between myocardial infarct size and the degree of PARP activation in circulating leukocytes. Another aim of the study was to test the effect of 3-aminobenzamide (a well-known and widely used PARP inhibitor) on the activation of PARP in the reperfused myocardium and peripheral leukocytes. Poly(ADP-ribose) polymerase activation was measured by Western blotting for its product, poly(ADP-ribose) (PAR). The localization of PARP activation was determined by PAR immunohistochemistry. The results showed that poly(ADP-ribosyl)ation was detected 15 min, peaked 2 to 6 h, and remained markedly detectable 24 h in the reperfused heart after I/R model. Similarly, PAR content of the leukocytes increased in cells isolated just after reperfusion from the same rat. Immunohistochemical studies localized the staining of PAR primarily to the cardiac myocytes and vascular endothelial cells. At 6 h, there was a significant linear correlation between infarct size and PARP activity, whereas at 2 and 24 h, no relationship was found. The PARP inhibitor 3-aminobenzamide (3-AB, 20 mg kg⁻¹ i.v. injection 15 min before reperfusion, and every 2 h thereafter for 6 h) markedly reduced infarct size through depressing the activation of the enzyme in myocytes and peripheral leukocytes even when the treatment is initiated at 2 h after reperfusion.

ROS‐Mediated PARP Activity Undermines Mitochondrial Function After Permeability Transition Pore Opening During Myocardial Ischemia–Reperfusion

“…In accordance with this model, PARP inhibitors have been shown to protect the myocardium and the brain even when administered up to 4 hours after reperfusion when infarct size was assessed at 24 hours . Our data therefore explain how PARP inhibition provides protection downstream of mPTP opening by revealing that mPTP‐mediated depolarization is not terminal in a significant fraction of the cells in the area at risk.…”

Therapeutic applications of PARP inhibitors: Anticancer therapy and beyond

“…3-AB significantly improved the outcome of myocardial dysfunction, as evidenced by a reduction in creatine phosphokinase levels, diminished infarct size, and preserved the ATP pools (Zingarelli et al, 1997). These findings were subsequently confirmed and extended into various other models using PARP inhibitors of increasing selectivity and potency (Thiemermann et al, 1997; Bowes et al, 1998a; Bowes et al, 1998b; Docherty et al, 1999; Liaudet et al, 2001a, Liaudet et al, 2001b, Faro et al, 2002; Zingarelli et al, 2003; Khan et al, 2003; Kaplan et al, 2005; Song et al, 2008; Eltze et al, 2008; Roesner et al, 2010; Zhang et al, 2012). Furthermore, Zingarelli also demonstrated that PARP deficient mice are protected against myocardial reperfusion injury (Zingarelli et al, 1998; Yang et al, 2000).…”

“…area at risk). Most of the poly(ADP-ribose) staining occurs in cardiac myocytes and endothelial cells, indicating that the heart tissue and the vasculature themselves are the main sites of PARP activation (Liaudet et al, 2001a; Liaudet et al, 2001b; Zhang et al, 2012). In addition, PARP activation also occurs in circulating mononuclear cells (Murthy et al, 2004; Toth-Zsamboki et al, 2006).…”

Discovery of new therapeutic redox targets for cardioprotection against ischemia/reperfusion injury and heart failure

“…Following I/R, increased oxidative and nitrosative stress activates the nuclear enzyme poly(ADP-ribose) polymerase (PARP), which catalyzes the cleavage of NAD + into nicotinamide and ADP-ribose [228]. NAD + depletion can interfere with glycolysis, the Krebs cycle, mitochondrial electron transport and lead eventually to ATP depletion.…”